Pathogen-Induced Inflammation in Platelet Function

虽然有证据表明，慢性炎症和感染促进斑块形成，急性 感染与不稳定的冠状动脉和血管疾病的风险短暂增加5倍有关。 血小板依赖性血栓形成引起的综合征。虽然许多细菌菌株诱导血小板 对于血小板聚集，细菌刺激血小板的机制的研究很少。在 利用全面的微阵列分析的初步数据，以及一个大型的社区队列， 在2,000名受试者中，我们发现心血管疾病患者血小板基因表达的不同模式， 疾病虽然在血小板中检测到几种TLR，但TLR 2和IL 1 R的表达尤其是在血小板中。 在心血管疾病患者中增加。重要的是，血小板中TLR的功能 血小板与TLR 2配体孵育剂量依赖性诱导血小板活化 和聚合。此外，我们发现血小板功能和血小板-单核细胞/中性粒细胞增加， 与C.肺炎杆菌感染和牙龈卟啉单胞菌孵育。的中心假设 总体计划项目是“病原体刺激通过先天免疫识别调节 炎症介质调节宿主免疫细胞功能，导致慢性炎症性疾病”。 项目1的中心假设是，细菌介导血栓前和炎症过程， 血小板通过先天免疫途径。为了研究这一假设，我们提出以下目标： 目标1。探讨TLR 2和IL-1 R在C.肺炎链球菌和牙龈卟啉单胞菌增强血小板聚集 功能 目标2.定义C.肺炎链球菌和牙龈卟啉单胞菌介导血小板中TLR 2和IL 1 R依赖性信号传导途径和巨核细胞中NF κ B依赖性转录的调节。 目标3.目的探讨TLR 2和IL-1 R在血小板对C. pneumoniae和P. 体内牙龈依赖性血栓形成。

While there is evidence that chronic inflammation and infection promotes plaque formation, acute infections are associated with a transient five-fold increased risk of unstable coronary and vascular syndromes caused by platelet dependent thrombosis. While many strains of bacteria induce platelet aggregation, the mechanisms by which bacteria stimulate platelets has had minimal investigation. In preliminary data utilizing comprehensive microarray analyses, and a large community cohort of almost 2,000 subjects, we found distinct patterns of platelet gene expression in patients with cardiovascular disease. While several TLRs were detected in platelets, the expression of TLR2 and IL1R in particular were increased in patients with cardiovascular disease. Importantly, the functionality of TLR in platelets was established as incubation of platelets with TLR2 ligands dose-dependently induced platelet activation and aggregation. In addition, we found enhanced platelet function and platelet-monocyte/neutrophil binding with C. pneumoniae infection in vivo, and P. gingivalis incubation. The central hypothesis of the overall program project is that "Pathogen stimulation via innate immune recognition modulates inflammatory mediator regulation of host immune cell function resulting in chronic inflammatory disorders". The central hypothesis of Project 1 is that bacteria mediate pro-thrombotic and -inflammatory processes in platelets via innate immune pathways. To investigate this hypothesis, we propose the following Aims: Aim 1. To define the role of TLR2 and IL-1R in C. pneumoniae and P. gingivalis enhanced platelet function. Aim 2. To define C. pneumoniae and P. gingivalis mediated modulation of TLR2- and IL1R-dependent signaling pathways in platelets and NFkappaB-dependent transcription in megakaryocytes. Aim 3. To define the role of TLR2 and IL-1 R in platelet specific responses to C. pneumoniae and P. gingivalis dependent thrombosis in vivo.